Use of dianhydrogalactitol and analogs or derivatives thereof in combination with platinum-containing antineoplastic agents to treat non-small-cell carcinoma of the lung and brain metastases

Abstract

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer, as well as other types of malignancy, including brain metastases of NSCLC. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.

What is claimed is: 
     
       1. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC; and 
 (b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC. 
 
     
     
       2. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC; 
 (b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, and 
 (c) resecting the NSCLC surgically subsequent to the administration of the dianhydrogalactitol and the platinum-based anti-neoplastic agent. 
 
     
     
       3. A method of treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent consisting of the steps of:
 (a) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC; 
 (b) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, and 
 (c) resecting the NSCLC surgically prior to the administration of the dianhydrogalactitol and the platinum-based anti-neoplastic agent. 
 
     
     
       4. The method of  claim 1  wherein the patient has brain metastases. 
     
     
       5. The method of  claim 1  wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered in a single pharmaceutical composition, wherein the pharmaceutical composition comprises: (i) dianhydrogalactitol; (ii) the platinum-based anti-neoplastic agent; and (iii) at least one pharmaceutically acceptable carrier. 
     
     
       6. The method of  claim 1  wherein the dianhydrogalactitol and the platinum-based anti-neoplastic agent are administered in two pharmaceutical compositions: (i) a first pharmaceutical composition comprising dianhydrogalactitol and at least one pharmaceutically acceptable carrier; and (ii) a second pharmaceutical composition comprising the platinum-based anti-neoplastic agent and at least one pharmaceutically acceptable carrier. 
     
     
       7. The method of  claim 1  wherein the patient has a wild-type p53 genotype. 
     
     
       8. The method of  claim 1  wherein the patient has a mutated p53 genotype. 
     
     
       9. The method of  claim 1  wherein the patient has a wild-type EGFR genotype. 
     
     
       10. The method of  claim 1  wherein the patient has at least one mutation in a gene encoding a protein that is a target of at least one tyrosine kinase inhibitor (TKI). 
     
     
       11. The method of  claim 1  wherein the patient is characterized by the presence of at least one gene in either a wild-type or mutated state encoding a product that confers resistance to the therapeutic effects of at least one tyrosine kinase inhibitor (TKI). 
     
     
       12. The method of  claim 11  wherein the gene in either a wild-type or mutated state encoding a product that confers resistance to the therapeutic effects of at least one TKI is AHI-1. 
     
     
       13. The method of  claim 12  wherein the AHI-1 gene is mutated as the result of a proviral insertion. 
     
     
       14. The method of  claim 1  wherein the patient is characterized by a mutation in the kinase domain of ABL1 protein that is part of a BCR-ABL fusion protein that is a target of TKIs. 
     
     
       15. The method of  claim 1  wherein the patient is characterized by a germline DNA deletion polymorphism conferring resistance to tyrosine kinase inhibitors (TKIs). 
     
     
       16. The method of  claim 15  wherein the germline DNA deletion polymorphism is a germline DNA deletion polymorphism of 2903 bp located in the BIM gene. 
     
     
       17. The method of  claim 16  wherein the germline DNA deletion polymorphism causes a splicing variation that leads to expression of an isoform of BIM protein that lacks a BH3 domain and thus inhibits the induction of apoptosis. 
     
     
       18. The method of  claim 1  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobaplatin, heptaplatin, and lipoplatin. 
     
     
       19. The method of  claim 18  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin. 
     
     
       20. The method of  claim 19  wherein the platinum-based anti-neoplastic agent is cisplatin. 
     
     
       21. The method of  claim 1  wherein the cytotoxic activity of dianhydrogalactitol and the platinum-based anti-neoplastic agent is higher than the cytotoxic activity of the dianhydrogalactitol administered at the same dosage as a single anti-neoplastic agent. 
     
     
       22. The method of  claim 21  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin. 
     
     
       23. The method of  claim 22  wherein the platinum-based anti-neoplastic agent is cisplatin. 
     
     
       24. A method for treating a patient with non-small cell lung cancer (NSCLC) resistant to a platinum-based anti-neoplastic agent, wherein the patient has a mutated p53 gene consisting of the steps of:
 (a) determining the existence of a mutated p53 gene in the patient, wherein the mutated p53 gene affects the resistance of the NSCLC to at least one platinum-based anti-neoplastic agent; 
 (b) administering a therapeutically effective quantity of dianhydrogalactitol to the patient to treat the NSCLC, wherein the therapeutically effective quantity of dianhydrogalactitol is determined from results on cell lines with a mutated p53 gene; and 
 (c) administering a therapeutically effective quantity of the platinum-based anti-neoplastic agent to the patient to treat the NSCLC, wherein the therapeutically effective quantity of the platinum-based anti-neoplastic agent is determined from results on cell lines with a mutated p53 gene. 
 
     
     
       25. The method of  claim 24 , wherein the existence of the mutated p53 gene in the patient is determined by a method selected from the group consisting of gene sequencing, restriction fragment length polymorphism, and determining whether p53 in a cell sample from the patient binds to a pGL3 vector. 
     
     
       26. The method of  claim 24 , wherein the method further comprises the step of administering a therapeutically effective quantity of a p53 mimetic to the patient to treat the NSCLC. 
     
     
       27. The method of  claim 24  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lobaplatin, heptaplatin, and lipoplatin. 
     
     
       28. The method of  claim 27  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin. 
     
     
       29. The method of  claim 28  wherein the platinum-based anti-neoplastic agent is cisplatin. 
     
     
       30. The method of  claim 24  wherein the cytotoxic activity of dianhydrogalactitol and the platinum-based anti-neoplastic agent is higher than the cytotoxic activity of the dianhydrogalactitol administered at the same dosage as a single anti-neoplastic agent. 
     
     
       31. The method of  claim 30  wherein the platinum-based anti-neoplastic agent is selected from the group consisting of cisplatin, carboplatin, and oxaliplatin. 
     
     
       32. The method of  claim 31  wherein the platinum-based anti-neoplastic agent is cisplatin. 
     
     
       33. The method of  claim 1 , wherein the combination of the therapeutically effective quantity of dianhydrogalactitol and the therapeutically effective quantity of the platinum-based anti-neoplastic agent act synergistically to treat the patient with NSCLC resistant to the platinum-based anti-neoplastic agent.